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Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials

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Abstract

Background

Inflammatory processes are involved in chronic diseases. It has been suggested that melatonin reduces inflammation by its radical scavenging properties; however, the results of the previous studies are inconclusive. The objective of the present meta-analysis is to determine the direction and magnitude of melatonin supplementation effect on inflammatory biomarkers.

Methods

Databases including PubMed, Scopus, Cochran Library, Embase, and Google Scholar were searched up to April 2019. Meta-analysis was performed using random-effect model. Subgroup analysis, sensitivity analysis, and meta-regression were also carried out.

Results

Thirteen eligible studies with 22 datasets with total sample size of 749 participants were included in the meta-analysis. Melatonin supplementation significantly decreased TNF-α and IL-6 levels [(WMD = − 2.24 pg/ml; 95% CI − 3.45, − 1.03; P < 0.001; I2 = 96.7%, Pheterogeneity < 0.001) and (WMD = − 30.25 pg/ml; 95% CI − 41.45, − 19.06; P < 0.001, I2 = 99.0%; Pheterogeneity < 0.001)], respectively. The effect of melatonin on CRP levels was marginal (WMD = − 0.45 mg/L; 95% CI − 0.94, 0.03; P = 0.06; I2 = 96.6%, Pheterogeneity < 0.001).

Conclusion

The results of the present meta-analysis support that melatonin supplementation could be effective on ameliorating of inflammatory mediators.

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References

  1. An R, Ji M, Zhang S (2018) Global warming and obesity: a systematic review. Obes Rev 19(2):150–163. https://doi.org/10.1111/obr.12624

    Article  CAS  PubMed  Google Scholar 

  2. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115(5):1111–1119. https://doi.org/10.1172/jci25102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee Y (2011) Relationship between inflammation biomarkers, antioxidant vitamins, and bone mineral density in patients with metabolic syndrome. Nutr Res Pract

  4. Devaraj S, Leonard S, Traber MG, Jialal I (2008) Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med 44(6):1203–1208. https://doi.org/10.1016/j.freeradbiomed.2007.12.018

    Article  CAS  PubMed  Google Scholar 

  5. Hoyos M, Guerrero JM, Perez-Cano R, Olivan J, Fabiani F, Garcia-Perganeda A et al (2000) Serum cholesterol and lipid peroxidation are decreased by melatonin in diet-induced hypercholesterolemic rats. J Pineal Res 28(3):150–155

    Article  CAS  PubMed  Google Scholar 

  6. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX (2000) Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci 917:376–386

    Article  CAS  PubMed  Google Scholar 

  7. Lissoni P, Pittalis S, Rovelli F, Roselli M, Ardizzoia A (1996) Modulation of cytokine production from TH2-lymphocytes and monocytes by the pineal neurohormone melatonin. Oncol Rep 3(3):541–543

    CAS  PubMed  Google Scholar 

  8. Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ (2011) Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 12(3):167–188. https://doi.org/10.1111/j.1467-789X.2010.00756.x

    Article  CAS  PubMed  Google Scholar 

  9. Higgins JP, Green S (2011) Cochrane handbook for systematic reviews of interventions, vol 4. Wiley

  10. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  Google Scholar 

  11. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  CAS  PubMed  Google Scholar 

  12. Wu Y, Zhang Q, Ren Y, Ruan Z (2017) Effect of probiotic Lactobacillus on lipid profile: a systematic review and meta-analysis of randomized, controlled trials. PLoS One 12(6):e0178868

    Article  PubMed  PubMed Central  Google Scholar 

  13. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics, pp 1088–1101

  14. Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mesri Alamdari N, Mahdavi R, Roshanravan N, Lotfi Yaghin N, Ostadrahimi AR, Faramarzi E (2014) A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res 47(7):504–508. https://doi.org/10.1055/s-0034-1384587

    Article  CAS  PubMed  Google Scholar 

  16. Javanmard SH, Heshmat-Ghahdarijani K, Mirmohammad-Sadeghi M, Sonbolestan SA, Ziayi A (2016) The effect of melatonin on endothelial dysfunction in patient undergoing coronary artery bypass grafting surgery. Adv Biomed Res 5:174. https://doi.org/10.4103/2277-9175.194801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pakravan H, Ahmadian M, Fani A, Aghaee D, Brumanad S, Pakzad B (2017) The effects of melatonin in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Adv Biomed Res 6:40. https://doi.org/10.4103/2277-9175.204593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Raygan F, Ostadmohammadi V, Bahmani F, Reiter RJ, Asemi Z (2017) Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: a randomized, double-blind, placebo-controlled trial. Clin Nutr. https://doi.org/10.1016/j.clnu.2017.12.004

    Article  PubMed  Google Scholar 

  19. Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F et al (2018) The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addict Biol. https://doi.org/10.1111/adb.12650

    Article  PubMed  Google Scholar 

  20. Bazyar H, Gholinezhad H, Moradi L, Salehi P, Abadi F, Ravanbakhsh M et al (2018) The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial. Inflammopharmacology. https://doi.org/10.1007/s10787-018-0539-0

    Article  PubMed  Google Scholar 

  21. Taghavi Ardakani A, Farrehi M, Sharif MR, Ostadmohammadi V, Mirhosseini N, Kheirkhah D et al (2018) The effects of melatonin administration on disease severity and sleep quality in children with atopic dermatitis: a randomized, double-blinded, placebo-controlled trial. Pediatr Allergy Immunol 29(8):834–840. https://doi.org/10.1111/pai.12978

    Article  PubMed  Google Scholar 

  22. Cichoz-Lach H, Celinski K, Konturek PC, Konturek SJ, Slomka M (2010) The effects of l-tryptophan and melatonin on selected biochemical parameters in patients with steatohepatitis. J Physiol Pharmacol 61(5):577–580

    CAS  PubMed  Google Scholar 

  23. Chojnacki C, Wisniewska-Jarosinska M, Walecka-Kapica E, Klupinska G, Jaworek J, Chojnacki J (2011) Evaluation of melatonin effectiveness in the adjuvant treatment of ulcerative colitis. J Physiol Pharmacol 62(3):327–334

    CAS  PubMed  Google Scholar 

  24. Celinski K, Konturek PC, Slomka M, Cichoz-Lach H, Brzozowski T, Konturek SJ et al (2014) Effects of treatment with melatonin and tryptophan on liver enzymes, parameters of fat metabolism and plasma levels of cytokines in patients with non-alcoholic fatty liver disease—14 months follow up. J Physiol Pharmacol 65(1):75–82

    CAS  PubMed  Google Scholar 

  25. Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F et al (1996) Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer 32a(8):1340–1343

  26. Forrest CM, Mackay GM, Stoy N, Stone TW, Darlington LG (2007) Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Br J Clin Pharmacol 64(4):517–526. https://doi.org/10.1111/j.1365-2125.2007.02911.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sanchez-Lopez AL, Ortiz GG, Pacheco-Moises FP, Mireles-Ramirez MA, Bitzer-Quintero OK, Delgado-Lara DLC et al (2018) Efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing remitting multiple sclerosis. Arch Med Res 49(6):391–398. https://doi.org/10.1016/j.arcmed.2018.12.004

    Article  CAS  PubMed  Google Scholar 

  28. Pittas AG, Joseph NA, Greenberg AS (2004) Adipocytokines and insulin resistance. J Clin Endocrinol Metab 89(2):447–452

    Article  CAS  PubMed  Google Scholar 

  29. Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Investig 111(12):1805–1812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Devaraj S, Singh U, Jialal I (2009) Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol 20(3):182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Janus A, Szahidewicz-Krupska E, Mazur G, Doroszko A (2016) Insulin resistance and endothelial dysfunction constitute a common therapeutic target in cardiometabolic disorders. Mediat Inflam

  32. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105(2):141–150

    Article  CAS  PubMed  Google Scholar 

  33. Seabra MDLV, Bignotto M, Pinto LR Jr, Tufik S (2000) Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 29(4):193–200

    Article  CAS  PubMed  Google Scholar 

  34. Reiter RJ, Maestroni GJ (1999) Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation. J Mol Med 77(1):36–39

    Article  CAS  PubMed  Google Scholar 

  35. Cuzzocrea S, Misko TP, Costantino G, Mazzon E, Micali A, Caputi AP et al (2000) Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. FASEB J 14(9):1061–1072

    Article  CAS  PubMed  Google Scholar 

  36. Cuzzocrea S, Reiter RJ (2002) Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem 2(2):153–165

    Article  CAS  PubMed  Google Scholar 

  37. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin—a pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93(3):350–384

    Article  CAS  PubMed  Google Scholar 

  38. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX (2000) Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci 917(1):376–386

    Article  CAS  PubMed  Google Scholar 

  39. Bertuglia S, Marchiafava P, Colantuoni A (1996) Melatonin prevents ischemia reperfusion injury in hamster cheek pouch microcirculation. Cardiovasc Res 31(6):947–952

    Article  CAS  PubMed  Google Scholar 

  40. Lloyd JK (1990) The importance of vitamin E in human nutrition. Acta Paediatr 79(1):6–11

    Article  CAS  Google Scholar 

  41. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51(1):1–16

    Article  CAS  PubMed  Google Scholar 

  42. Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 54(1):1–14

    Article  CAS  PubMed  Google Scholar 

  43. Ghosh AK, Naaz S, Bhattacharjee B, Ghosal N, Chattopadhyay A, Roy S et al (2017) Mechanism of melatonin protection against copper-ascorbate-induced oxidative damage in vitro through isothermal titration calorimetry. Life Sci 180:123–136

    Article  CAS  PubMed  Google Scholar 

  44. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61(3):253–278

    Article  CAS  PubMed  Google Scholar 

  45. Boulangé CL, Neves AL, Chilloux J, Nicholson JK, Dumas M-E (2016) Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome medicine 8(1):42

    Article  PubMed  PubMed Central  Google Scholar 

  46. Torres-Fuentes C, Schellekens H, Dinan TG, Cryan JF (2017) The microbiota–gut–brain axis in obesity. Lancet Gastroenterol Hepatol 2(10):747–756

    Article  PubMed  Google Scholar 

  47. Thaiss CA, Levy M, Korem T, Dohnalová L, Shapiro H, Jaitin DA et al (2016) Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167(6):1495–1510. e12

  48. Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV (2017) The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357(6354):912–916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ma N, Zhang J, Reiter RJ, Ma X (2019) Melatonin mediates mucosal immune cells, microbial metabolism, and rhythm crosstalk: a therapeutic target to reduce intestinal inflammation. Med Res Rev

  50. Yildirim A, Tamer SA, Sahin D, Bagriacik F, Kahraman MM, Onur ND et al (2019) The effects of antibiotics and melatonin on hepato-intestinal inflammation and gut microbial dysbiosis induced by a short term high-fat diet consumption in rats. Br J Nutr 1–31

  51. Chen C-Q, Fichna J, Bashashati M, Li Y-Y, Storr M (2011) Distribution, function and physiological role of melatonin in the lower gut. WJG 17(34):3888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Alamdari NM, Mahdavi R, Roshanravan N, Yaghin NL, Ostadrahimi A, Faramarzi E (2015) A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women. Horm Metab Res 47(07):504–508

    Google Scholar 

  53. Forrest CM, Mackay GM, Stoy N, Stone TW, Darlington LG (2007) Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Br J Clin Pharmacol 64(4):517–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ferracioli-Oda E, Qawasmi A, Bloch MH (2018) Meta-Analysis: melatonin for the treatment of primary sleep disorders. Focus 16(1):113–118

    Article  PubMed  PubMed Central  Google Scholar 

  55. Akbari M, Ostadmohammadi V, Tabrizi R, Lankarani KB, Heydari ST, Amirani E et al (2018) The effects of melatonin supplementation on inflammatory markers among patients with metabolic syndrome or related disorders: a systematic review and meta-analysis of randomized controlled trials. Inflammopharmacology 26(4):899–907. https://doi.org/10.1007/s10787-018-0508-7

    Article  CAS  PubMed  Google Scholar 

  56. Henderson R, Kim S, Lee E (2018) Use of melatonin as adjunctive therapy in neonatal sepsis: a systematic review and meta-analysis. Complement Ther Med 39:131–136. https://doi.org/10.1016/j.ctim.2018.06.002

    Article  PubMed  Google Scholar 

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Correspondence to Ahmad Saedisomeolia or Shahab Alizadeh.

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Zarezadeh, M., Khorshidi, M., Emami, M. et al. Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials. Eur J Nutr 59, 1803–1813 (2020). https://doi.org/10.1007/s00394-019-02123-0

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